Penn Researchers Make Major Advancement
in Lou Gehrig’s Disease and FTDIdentifying Disease Protein for Two Common Neurodegenerative
Disorders
Will Mean Better Treatments

(Philadelphia, PA) - Researchers at the University of Pennsylvania
School of Medicine have discovered the major disease protein
for two neurodegenerative disorders: a type of frontotemporal dementia
(FTD) and amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s
disease. A protein called TDP-43 was found to accumulate abnormally in
post-mortem brain tissue from individuals diagnosed with either disease.
The misfolded, disease protein was recovered from only affected central
nervous system regions, which include the hippocampus, neocortex, and
spinal cord.

These findings open up new avenues of research into how the crumpling,
or misfolding, of specific brain proteins (TDP-43) leads to strange, and
sometimes even criminal behavior (in FTD), as well as paralysis (in ALS),
which depends upon whether these toxic waste products get dumped in the
frontal and temporal lobes (the part of brain controlling judgment and
comportment), or the spinal cord motor neurons (the control centers regulating
the ability to walk, run, and other types of movement).

A connection between these two disorders has long been sought and TDP-43
is the common pathologic protein linking them. The researchers published
their findings in the October 6, 2006 issue of Science, and have
resolved a long-standing mystery that many consider one of the last major
enigmas about the relationship of FTD to ALS.

“It’s very exciting that we finally made the connection between
dementia and motor neuron disease,” says Virginia Lee, PhD,
Director of the Center for Neurodegenerative Disease Research at Penn.
FTD is a complex group of disorders -clinically, genetically, and pathologically
- and is the most common cause of dementia in people under the age of
65, after Alzheimer’s disease. Progressive changes in social, behavioral,
and language skills are part of FTD; some patients also develop motor
neuron disease. In some patients diagnosed with ALS - a progressive neurological
disorder that destroys motor neurons - dementia can also be a later complication.

While most people have heard of ALS because it affected baseball great
Lou Gehrig, fewer people have heard of FTD; it is less common, overall,
than other dementias such as Alzheimer’s disease. “However,
another reason for FTD’s relative obscurity is also undoubtedly
the shame family members experience with the strange and, at times, bizarre
behavior of patients, including disturbing obsessions, larceny, or even
sexual deviancy, that may bring the patient to the attention of the legal
system rather than to the healthcare system,” notes coauthor John
Trojanowksi, MD, PhD, Director of the Institute on Aging at Penn.

Misfolded proteins are a common mechanism in neurodegenerative diseases.
The misfolded proteins are tagged for recycling by the cell with another
protein called ubiquitin. However, in neurodegenerative diseases these
tagged proteins aggregate in the neurons of the brain and spinal cord
and act like toxic waste dumps that become progressively more widespread
and toxic. Many misfolded disease proteins have been identified and targeted
for drug development in other neurodegenerative disorders; however, identifying
the disease protein in the most common form of FTD and ALS remained elusive.

“Clinically there’s overlap in these two disorders, so it
was very tantalizing to see if there was anything to link them biochemically,”
says Lee. Indeed, this overlap suggested different manifestations of the
same disorder.

To identify the protein, the group first made antibodies to the tagged,
misfolded protein common to tissue samples from both disorders. “We
then took brain extract containing the mystery protein and injected it
into mice to develop the monoclonal antibodies that recognize TDP-43,”
explains Lee. The researchers then used antibodies against TDP-43 in post-mortem
brain tissue samples and found that all 72 cases of FTD or ALS examined
contained misfolded TDP-43. “Since many cases were studied, the
data became very compelling,” recalls Lee.

TDP-43 is a known protein with multiple functions and is widely expressed
throughout the body, in the nucleus of many cell types. Its function has
been implicated in editing the transcription of the genetic code and also
as a scaffold protein for another motor neuron protein. The discovery
that TDP-43 is the disease protein in the most common form of FTD and
ALS will drive renewed efforts to discover more effective treatments for
these otherwise lethal diseases.

This research was funded by the National Institute on Aging. Coauthors,
in addition to Lee and Trojanowski, are first authors Manuela Neumann,
Deepak M. Sampathu, and Linda K. Kwong, all from Penn, as well as Matthew
C. Micsenyi, Thomas T. Chou, Jennifer Bruce, Theresa Schuck, Murray Grossman,
Christopher M. Clark, and Leo F. McCluskey, also from Penn. Bruce L. Miller,
University of California, San Francisco; Eliezer Masliah, UC, San Diego;
Ian R. Mackenzie and Howard Feldman, University of British Columbia; Wolfgang
Feiden, University of Saarland (Homburg); and Hans A. Kretzschmar, Ludwig-Maximilians
University (Munich) were also coauthors.

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